tbuckley/cabot-search huggingface dataset:
Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure
Authors: Jing Ma, Adrien Guillot, Zhihong Yang, Bryan Mackowiak, Seonghwan Hwang, Ogyi Park, Brandon J. Peiffer, Ali Reza Ahmadi, Luma Melo, Praveen Kusumanchi, Nazmul Huda, Romil Saxena, Yong He, Yukun Guan, Dechun Feng, Pau Sancho-Bru, Mengwei Zang, Andrew MacGregor Cameron, Ramon Bataller, Frank Tacke, Zhaoli Sun, Suthat Liangpunsakul, Bin Gao
Journal: Journal of Clinical Investigation (2022)

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neuhi), but low levels of CD8+ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neuhi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.
Microbially derived polyunsaturated fatty acid as a modulator of gastrointestinal motility
Authors: Yang Xiao, Purna C. Kashyap
Journal: Journal of Clinical Investigation (2022)

Gastrointestinal (GI) motility requires coordination among several cell types in the intestinal epithelium and the neuromuscular apparatus. A disruption in GI motility was primarily attributed to disruption of this coordinated effort among different host cells, but recent studies have begun to uncover how the products of gut microbiota can alter GI motility by modulating the function of different host cells and the interactions among them. In this issue of the JCI, Chen, Qiu, et al. used a reverse translation approach, isolating a Shigella sp. - peristaltic contraction-inhibiting bacterium (PIB) - from a cohort of patients with intractable constipation. They identified an ω-3 polyunsaturated fatty acid (PUFA), docosapentaenoic acid (DPA), produced by this Shigella variant, as an important driver of constipation using a series of microbiologic, biochemical, and genetic manipulations combined with in vitro and in vivo studies. This finding advances the field, given that production of DPA is rare in the human gut and appears to have a distinct effect on GI physiology.
Connecting aging biology and inflammation in the omics era
Authors: Keenan A. Walker, Nathan Basisty, David M. Wilson, Luigi Ferrucci
Journal: Journal of Clinical Investigation (2022)

Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging - and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.
Creatine riboside is a cancer cell–derived metabolite associated with arginine auxotrophy
Authors: Amelia L. Parker, Leila Toulabi, Takahiro Oike, Yasuyuki Kanke, Daxeshkumar Patel, Takeshi Tada, Sheryse Taylor, Jessica A. Beck, Elise Bowman, Michelle L. Reyzer, Donna Butcher, Skyler Kuhn, Gary T. Pauly, Kristopher W. Krausz, Frank J. Gonzalez, S. Perwez Hussain, Stefan Ambs, Bríd M. Ryan, Xin Wei Wang, Curtis C. Harris
Journal: Journal of Clinical Investigation (2022)

The metabolic dependencies of cancer cells have substantial potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is identified as a urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high CR levels in patients with cancer as well as their implications for the treatment of these aggressive cancers remain unclear. By integrating multiomics data on lung and liver cancer, we have shown that CR is a cancer cell-derived metabolite. Global metabolomics and gene expression analysis of human tumors and matched liquid biopsies, together with functional studies, revealed that dysregulation of the mitochondrial urea cycle and a nucleotide imbalance were associated with high CR levels and indicators of a poor prognosis. This metabolic phenotype was associated with reduced immune infiltration and supported rapid cancer cell proliferation that drove aggressive tumor growth. CRhi cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of CR not only as a poor-prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve survival for patients with cancer.
KRAS mutations as essential promoters of lymphangiogenesis via extracellular vesicles in pancreatic cancer
Authors: Radu Pirlog, George A. Calin
Journal: Journal of Clinical Investigation (2022)

Kirsten rat sarcoma virus (KRAS) gene mutations are present in more than 90% of pancreatic ductal adenocarcinomas (PDACs). KRASG12D is the most frequent alteration, promoting preneoplastic lesions and associating with a more aggressive phenotype. These tumors possess increased intratumoral lymphatic networks and frequent lymph node (LN) metastases. In this issue of the JCI, Luo, Li, et al. explored the relationship between the presence of the KRASG12D mutation and lymphangiogenesis in PDAC. The authors used in vitro and in vivo models and an elegant mechanistic approach to describe an alternative pathway for lymphangiogenesis promotion. KRASG12D induced SUMOylation of heterogenous nuclear ribonucleoprotein A1 (hnRNPA1) via SAE1 and SUMO2 activation. SUMOylated hnRNPA1 was loaded into extracellular vesicles (EVs) and internalized by human endothelial lymphatic cells (HLEC). Further, SUMOylated hnRNPA1 promoted lymphangiogenesis and LN metastasis by stabilizing prospero homeodomain protein 1 (PROX1) mRNA. These data provide mechanistic insight into cancer lymphangiogenesis with the potential for developing biomarkers and RAS pathway therapeutics.
Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia
Authors: Edward J. Evans, James DeGregori
Journal: Journal of Clinical Investigation (2022)

Individuals with Down syndrome (DS) have more than 100-fold increased risk of acute megakaryoblastic leukemia (AMKL), but its pathogenesis is poorly understood. In this issue of the JCI, Arkoun et al. engineered stepwise DS-AMKL-associated mutations in GATA1, MPL, and SMC3 in human induced pluripotent stem cell (iPSC) clones from individuals with DS to dissect how each mutation affects gene expression control and megakaryocytic differentiation. The authors showed that the mutations cooperatively promote progression from transient myeloproliferative disorder to DS-AMKL. This study highlights the importance of mutation order and context in the perturbations of transcriptional and differentiation pathways involved in the evolution of hematologic malignancies, which will be critical for the development of preventative and therapeutic interventions.
Genetic mechanism for the loss of PRAME in B cell lymphomas
Authors: Marek Mraz
Journal: Journal of Clinical Investigation (2022)

To the Editor: Takata et al. (1) reported that patients with diffuse large B cell lymphoma (DLBCL) relatively frequently (13% of patients) harbor a deletion at the 22q11.22locus that involves the PRAME gene, and that PRAME loss is associated with poor outcomes and leads to cytotoxic T cell immune escape.The authors comment that "deletions...were located close to the Igλ gene."I would like to bring to the attention of the authors and readers that the PRAME gene and neighboring ZNF280A, ZNF280B, and GGTLC2 genes are located between variable (V) subgenes for the immunoglobulin lambda (Igλ) light chain (Figure 1).The PRAME deletion is inevitable when a B lymphocyte (normal or malignant) rearranges the Igλ locus and utilizes one of the many V subgenes located more distantly from the J-C region.It is known that approximately 30% to 40% of B lymphocytes express Igλ (~60%-70% express Igκ, since this locus for the Ig light chain is rearranged before Igλ).Therefore, it is not surprising that the loss of PRAME has been previously noted in multiple B cell malignancies, especially chronic lymphocytic leukemia (2-4).Takata et al. ( 1) observed that patients with PRAME deletions more often have an Igλ rearrangement, but they also report cases of DLBCL with a PRAME deletion and rearranged Igκ.However, it is not clear if in such cases the Igκ rearrangement was productive and what the status of the Igλ locus was.A defective allelic exclusion process might lead to Igκ and Igλ expression in one B cell.PRAME deletion associates with prognosis in DLBCL ( 1), but it should be considered that such a deletion could also be viewed as a surrogate marker for the use of one of the distal Igλ V subgenes (Figure 1), and it is known that Igλ usage associates with prognosis and B cell receptor (BCR) pathway deregulation in B cell malignancies (5).In summary, loss of PRAME is an expected phenomena in a portion of normal or malignant B cells with Igλ rearrangement.It remains puzzling why in evolution PRAME has been placed between Igλ subgenes and why its expression is activated in DLBCL.
<i>Notes from the Field:</i> Outbreak of <i>Salmonella</i> Enteritidis at a Correctional Facility Using Mechanically Separated Chicken — Nebraska, 2022
Authors: Sadie J. Oppegard, Andrea R. Bethke, Benjamin A. Davy, Ashley E. Johnson, Justin L. Daniel, Scott E. Holmes
Journal: MMWR Morbidity and Mortality Weekly Report (2022)
Public Health Surveillance and Reporting for Human Toxoplasmosis — Six States, 2021
Authors: Jayden McCall, Laura Rothfeldt, Kelly Giesbrecht, Amanda Hunt, Leah Bauck, Joni Scheftel, Rachael Birn, Bryan Buss, Betsy Schroeder, Thomas E. Haupt, Rachel Klos, Anne Straily
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Toxoplasmosis is caused by infection with the zoonotic parasite Toxoplasma gondii. Although disease tends to be mild (e.g., self-limiting influenza-like symptoms) or asymptomatic in immunocompetent persons, toxoplasmosis is more severe in immunocompromised persons, who can develop potentially fatal encephalopathy (1). In addition, primary infections acquired during pregnancy might result in a range of adverse outcomes, including fetal ocular infection, cranial and neurologic deformities, stillbirth, and miscarriage (1,2). An estimated 11% of the U.S. population aged ≥6 years are seropositive for toxoplasmosis, based on analysis of sera collected through the National Health and Nutrition Examination Survey during 2011-2014 (3). Toxoplasmosis is not a nationally notifiable disease in the United States, and currently no national public health surveillance data are available; however, it is reportable in eight states. To better understand how surveillance data are collected and used, reviews of state-level toxoplasmosis surveillance were conducted during June-July 2021 using semistructured interviews with health officials in six states (Arkansas, Kentucky, Minnesota, Nebraska, Pennsylvania, and Wisconsin) where toxoplasmosis is currently reportable. Why or when toxoplasmosis became reportable could not be determined, and many of the states had limited capacity to respond to reported cases. Case definitions varied considerably in terms of clinical description, laboratory criteria, and case classification (i.e., confirmed, probable, or suspect), limiting disease estimates and comparisons among states. Implementation of a standardized case definition would help ensure that cases are counted consistently, enabling better use of surveillance data to characterize disease. Identifying newly acquired cases is challenging because most acute cases among immunocompetent persons (including pregnant women) are asymptomatic, disease among immunocompromised persons is likely reactivation of latent disease, and congenital infections might not manifest until later in life.
Genetic mechanism for the loss of PRAME in B cell lymphomas. Reply.
Authors: Katsuyoshi Takata, Christian Steidl
Journal: Journal of Clinical Investigation (2022)

We thank Dr. Mraz for insightful comments that provide additional context to the findings in our study, in particular bringing to the forefront studies in other B cell malignancies including chronic lymphocytic leukemia (CLL) (1).As pointed out in the Letter by Dr. Mraz and discussed in our manuscript, PRAME deletions were significantly associated with Ig-λ rearrangements, and this finding is consistent with a mechanism in which PRAME deletions can occur in the context of rearrangement of variable (V) gene loci on chromosome 22 in a subset of patients (2).For this reason, we studied frequencies and treatment outcomes for PRAME deletions in the context of Ig-λ expression, as shown in Figure 1 (2).In particular, we demonstrate that PRAME deletions are independently associated with outcomes in multivariable analysis, making it unlikely that PRAME deletions are a pure surrogate for the prognostic effects of Ig-λ usage.As described by Mraz and Pospisilova, the association of PRAME deletion and Ig-λ rearrangement and expression is not absolute, and PRAME deletion is likely dependent on the exact V segment usage (3).Consistently, we did not observe PRAME deletions in the majority of patients expressing Ig-λ, and, interestingly, a minority of patients with PRAME deletions expressed Ig-κ.Indeed, it remains an open question whether heterozygous or homozygous PRAME deletions can occur during the process of B cell lymphomagenesis, and potentially at the time point of the germinal center (GC) reaction in GC-derived diffuse large B cell lymphomas (DLBCLs).Regardless of the deletion-generating mechanism, our study brings into focus PRAME loss-associated cell-autonomous and tumor microenvironment phenotypes that are under selective pressure in DLBCL.Our discovery that both genomic PRAME deletion and EZH2 mutations converge on reduced PRAME expression and downstream phenotypes underscores the pathogenic relevance of the PRAME gene in B cell lymphoma.
Safety Monitoring of COVID-19 mRNA Vaccine First Booster Doses Among Persons Aged ≥12 Years with Presumed Immunocompromise Status — United States, January 12, 2022–March 28, 2022
Authors: Anne M. Hause, James Baggs, Paige Marquez, Winston E. Abara, Jane Gwira Baumblatt, Deborah Thompson, John R. Su, Tanya R. Myers, Julianne Gee, Tom T. Shimabukuro, David K. Shay
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Persons with moderate to severe immunocompromising conditions are at risk for severe COVID-19, and their immune response to COVID-19 vaccination might not be as robust as the response in persons who are not immunocompromised* (1). The Advisory Committee on Immunization Practices (ACIP) recommends that immunocompromised persons aged ≥12 years complete a 3-dose primary mRNA COVID-19 vaccination series followed by a first booster dose (dose 4) ≥3 months after dose 3 and a second booster dose (dose 5) ≥4 months after dose 4.† To characterize the safety of first booster doses among immunocompromised persons aged ≥12 years during January 12, 2022-March 28, 2022, CDC reviewed adverse events and health impact assessments reported to v-safe and the Vaccine Adverse Event Reporting System (VAERS) during the week after receipt of an mRNA COVID-19 first booster dose. V-safe is a voluntary smartphone-based safety surveillance system for adverse events after COVID-19 vaccination. VAERS is a passive surveillance system for all vaccine-associated adverse events co-managed by CDC and the Food and Drug Administration (FDA). A fourth mRNA dose reported to v-safe or VAERS during January 12, 2022-March 28, 2022, was presumed to be an mRNA COVID-19 vaccine booster dose administered to an immunocompromised person because no other population was authorized to receive a fourth dose during that period (2,3). In the United States, during January 12, 2022-March 28, 2022, approximately 518,113 persons aged ≥12 years received a fourth dose. Among 4,015 v-safe registrants who received a fourth dose, local and systemic reactions were less frequently reported than were those following dose 3 of their primary series. VAERS received 145 reports after fourth doses; 128 (88.3%) were nonserious and 17 (11.7%) were serious. Health care providers, immunocompromised persons, and parents of immunocompromised children should be aware that local and systemic reactions are expected after a first booster mRNA COVID-19 vaccine dose, serious adverse events are rare, and safety findings were consistent with those previously described among nonimmunocompromised persons (4,5).
Role of Patient-Reported Outcome Measures in the Inpatient Setting
Authors: Abdulla Al-Rashdan
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Effects of enhanced recovery after surgery plus pulmonary rehabilitation on complications after video-assisted lung cancer surgery: a multicentre randomised controlled trial
Authors: Yu Zheng, Mao Mao, Fang Li, Lu Wang, Xintong Zhang, Xiu Zhang, Haiming Wang, Huiqing Zhou, Meifang Ji, Yulong Wang, Liang Liu, Quan Zhu, Jan D Reinhardt, Xiao Lu
Journal: Thorax (2022)

Background Lung cancer surgery is associated with a high incidence of postoperative pulmonary complications (PPCs). We evaluated whether enhanced recovery after surgery plus pulmonary rehabilitation was superior over enhanced recovery after surgery alone in reducing the incidence of postoperative PPCs and length of hospital stay. Methods In this pragmatic multicentre, randomised controlled, parallel-group clinical trial, eligible patients scheduled for video-assisted lung cancer surgery were randomly assigned (1:1) to either a newly developed programme that integrated preoperative and postoperative pulmonary rehabilitation components into a generic thoracic enhanced recovery after surgery pathway, or routine thoracic enhanced recovery after surgery. Primary outcome was the overall occurrence of PPCs within 2 weeks after surgery. Secondary outcomes were the occurrence of specific complications, time to removal of chest drain, and length of hospital stay (LOS). Results Of 428 patients scheduled for lung cancer surgery, 374 were randomised with 187 allocated to the experimental programme and 187 to control. Incidence of PPCs at 14 Days was 18.7% (35/187) in the experimental group and 33.2% (62/187) in the control group (intention-to-treat, unadjusted HR 0.524, 95% CI 0.347 to 0.792, p=0.002). Particularly, significant risk reduction was observed regarding pleural effusion, pneumonia and atelectasis. Time to removal of chest drain and LOS were not significantly reduced in the experimental group. Conclusions Adding pulmonary rehabilitation to enhanced recovery after surgery appears to be effective in reducing the incidence of PPCs, but not LOS. Standard integration of pulmonary rehabilitation into thoracic enhanced recovery after surgery is a promising approach to PPC prophylaxis. Trial registration number ChiCTR1900024646.
Trial of Erythropoietin for Hypoxic–Ischemic Encephalopathy in Newborns
Authors: Yvonne W. Wu, Bryan A. Comstock, Fernando F. Gonzalez, Dennis E. Mayock, Amy M. Goodman, Nathalie L. Maitre, Taeun Chang, Krisa P. Van Meurs, Andrea L. Lampland, Ellen Bendel-Stenzel, Amit M. Mathur, Tai-Wei Wu, David Riley, Ulrike Mietzsch, Lina Chalak, John Flibotte, Joern-Hendrik Weitkamp, Kaashif A. Ahmad, Toby D. Yanowitz, Mariana Baserga, Brenda B. Poindexter, Elizabeth E. Rogers, Jean R. Lowe, Karl C.K. Kuban, T. Michael O’Shea, Jessica L. Wisnowski, Robert C. McKinstry, Stefan Bluml, Sonia Bonifacio, Kristen L. Benninger, Rakesh Rao, Christopher D. Smyser, Gregory M. Sokol, Stephanie Merhar, Michael D. Schreiber, Hannah C. Glass, Patrick J. Heagerty, Sandra E. Juul
Journal: New England Journal of Medicine (2022)

Neonatal hypoxic–ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic–ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.
APR-246 triggers ferritinophagy and ferroptosis of diffuse large B-cell lymphoma cells with distinct TP53 mutations
Authors: Yuheng Hong, Tianyuan Ren, Xiaoxuan Wang, Xia Liu, Yue Fei, Shen Meng, Xu Han, Cong Sun, Hongru Shen, Lanfang Li, Lihua Qiu, Zhengzi Qian, Shiyong Zhou, Huilai Zhang, Xianhuo Wang
Journal: Leukemia (2022)